Approximately 80,000 new cases of mild traumatic brain injury are admitted to emergency units in France annually. Although most patients recover completely within weeks or months, approximately 10–25% (1–13) will have persisting symptoms with social and vocational consequences that appear disproportionate to the severity of the initial neurologic trauma (10). Such findings are now known as post-concussive syndrome (PCS). Symptoms include somatic, cognitive, and emotional complaints such as headache, sleep disturbances, balance disorders, cognitive impairment, fatigue, and mood or behavioral disorders.

Such persisting symptoms can affect patient outcomes in all aspects of life, with significant consequences with regard for public health (14–16).

Over the past decade, investigators have highlighted the role of predictive factors for the development and persistence of PCS. These factors can be pre-traumatic, related to the trauma itself, or post-traumatic. According to a critical review of the literature by Carroll and colleagues (WHO, Collaborating Centre Task Force on Mild Traumatic Brain Injury, 2004) (8), factors predicting PCS (with variable degrees of evidence) are divided into three categories:

The person: female gender, married status, enrolled in school, age over 40 years, pre-existing physical handicap, prior cerebral disease or neurological problem, prior head injuries, psychiatric problems, and major life stressors.

Seeking compensation and/or litigation were identified as important factors in patients with persisting symptoms.

Most recently, Cassidy and co-workers showed that more acute symptoms, poorer premorbid mental and physical health, and a major acute life stressor could predict persistent symptoms (13). Ponsford and associates also demonstrated the importance of premorbid psychiatric problems such as anxiety (17). However, literature pertaining to prognosis following MTBI varies substantially in quality, with multiple biases identified (8). The identification of corroborated risk factors could allow earlier and better-tailored treatment plans, and potentially decrease the incidence of persistent PCS.

We wished to demonstrate the potential value of a comprehensive neuropsychological complaints and quality of life (QoL) evaluation to identify early prognostic factors for MTBI patients, and to establish short clinical assessment tools applicable during the early stage of MTBI for patients susceptible to develop PCS.

This study was designed to identify early risk factors of UE following MTBI. We compared patients with FE and UE at early and late time points, and then developed univariate and multivariate logistic regression models. All MTBI subjects presented with disturbances in all domains evaluated at the early time point. In agreement with other studies, several areas were affected at this early time point after a MTBI; the affected areas were greater in number and effect and covered all domains evaluated in the unfavorable group compared with the FE group (13, 31, 32).

The univariate logistic regression model confirmed the absence of specificity of these disturbances; the large majority of scores obtained for each variable correlated with the prognosis. These results are in agreement with studies evaluating a large range of symptoms covering different domains (5, 7, 13, 32–35).

The multivariate model was then used with the 20 variables that exhibited the most robust correlation, as identified using the univariate model (p < 0.01). Three groups of early prognostic factors for PCS were identified: complaints, evaluation of QoL, and cognitive function determined by neuropsychological tests. Despite strong statistical power (Table 6), the reliable intervals are too large, limiting the reliability of this classification. To overcome this finding limitation, we developed a proposal extent model using a wider range of variables, to identify MTBI at risk of UE. This extent model was able to identify 95.7% of MTBI subjects with PCS at 6 months, as defined by the DSM-IV classification.

Above all, this result confirms the importance of the subjective elements identified in the RPCQ symptom questionnaire and the QoL evaluations. Although this domain is often undervalued or ignored, we demonstrate here that it allows direct access to the level of suffering experienced by MTBI patients. Our results demonstrate that the number of symptoms and the degree of discomfort are significantly higher for the unfavorable group at the early time point, and that QoL is the more significantly altered component.

The notion of QoL covers several domains reflecting subjective perceptions by an individual. Evaluation of QoL is an indicator of interest reflecting the patient’s self-perception, which is often the only element that allows the clinician to determine differences in pre- and post-traumatic states. Emanuelson and associates (31) demonstrated this by evaluating QoL and PCS progression; they concluded that the QoL measure allows evaluation of MTBI, as it correlates strongly with the presence of PCS.

The unfavorable group exhibited greater cognitive dysfunction regarding both low-level and high-level treatments. Our multivariate logistic regression model and the extent model support the role of cognitive performance in predicting PCS. This is of particular interest, as few studies to date have confirmed the extent of early cognitive deficits in MTBI patients at risk of UE. Ponsford and co-workers (17) demonstrated that at one week and three months after MTBI, cognitive factors were not predictive of PCS, and this finding was confirmed in a meta-analysis of the literature conducted by Cassidy and colleagues (13). Nonetheless, other groups have reported cognitive difficulties to be an early marker for more difficult recovery: in both the Wojcik model (36) and the earlier model of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury (8). These studies demonstrated that the presence of memory disturbances is a risk factor for slow recovery.

Functional MRI studies have revealed greater activation in the brain areas implicated in memory when symptoms are more severe at an earlier stage after MTBI (37, 38). Mathias and Coats (39) showed that MTBI patients performed worse than healthy volunteers in an evaluation of verbal phonemic fluency, a variable that was also identified in our multivariate logistic analysis. These results were confirmed by Goldstein and Levin in 2001 for the same test (40). The absence of specificity of cognitive deficits may be explained by the concomitant presence of alterations in attention treatments and a slowing of information processing, which may, in turn, cause a more global type of cognitive dysfunction observed from an early stage as reported by Azouvi and associates (41).

Thus, PCS appears to be dependent on a multidimensional system whose configuration can be specific from one individual to the next. This is not particularly surprising when one considers interactions as inter-dimensional, because affecting any one dimension will result in repercussions in all of the other dimensions. The Steptoe model (42) takes into account the different interactions of bio-psycho-social factors after a stressful situation, such as an accident.

It is also recognized that anxiety disorders can affect cognitive performance, such as attention processing or the coding of information by memory (43–45). A depressive state can also affect attention processing (46), slow information processing, disturb encoding functioning and the recovery of verbal information (47), and affect verbal phonemic fluency (48).

Pain, which also affects other domains, is common after MTBI (4, 33, 49). Our multivariate logistic regression model did not identify pain as a prognostic factor. This is in agreement with other studies that do not consider pain a prognostic factor of UE (11, 13, 36). Meares and co-workers (50) suggest that pain is more likely to be associated with early PCS than with persistent PCS. Therefore, our prognostic model that does not integrate pain as a factor is consistent with integrated predictive models such as the “diasthesis-stress paradigm” proposed by Wood (9), and with other earlier models such as that of the European Federation of Neurological Societies (EFNS, Task Force, 2002) (51), which reports three domains of related risk factors: the patient, the violence of the trauma, and the initial severity (51).

Our results show well the evolution of the symptoms that in the acute stage are most frequently organic disorder to evolve toward in the latest stage most frequently mood, QoL, and the cognitive functioning disorder. We also notice that the “subjective” indicators are particularly interesting to identify prematurely a risk of UE following the example of organic indicators. These results are in the same line of recent systematic review of the literature of Cassidy and associates (13). They suggest that the persistency of the symptoms would more be connected to the psychosocial factors, a number of symptoms for the acute stage, and the presence of emotional stress.

Post-concussive syndrome is a complex condition. Our results demonstrate the need for a multidimensional approach based on cognitive, somatic/mood, and QoL features in order to ensure the initial care of MTBI patients and the early identification of PCS. In this study, prognostic categories included the patients’ symptoms, QoL, and cognitive performances. The primary objective of this study, to identify early predictive factors of higher risk of UE in order to establish an effective diagnostic tool, was attained via the design of a prognostic grid. The prognostic tool devised will allow systematic evaluation of MTBI patients with respect to several features in order to rapidly identify the risk of developing PCS, both qualitatively and quantitatively, and customize care accordingly. It will also assist with further research into the efficacy of early care for MTBI patients.

The study was approved by the Ethics Committee of the Pitié-Salpêtrière University Hospital (ID RCB: 2008-A01542-53, Paris, France).

All authors were involved in the drafting of the manuscript or revising it critically for important intellectual content to include the final approval of this version for publication. SC, SB, NA, SM, and MM substantially contributed to the conception and design of the work, and analysis and interpretation of data. SC, SB, and NA substantially contributed to the acquisition of data. All agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. There were no competing financial interests. Funding from GMF excluded any recommendations or restraints regarding methodology, results, and publications.